In 1965, Gold and Fredman from Canada used extract from human colon cancer to immunize rabbit, and the obtained serum was used to examine various human tissues. It was then discovered that the digestic tract tumor originated from human endoderm are strongly positive for staining, and it was also discovered that the digestic tract tissue of 2-6 months old fetus is also positive, and thus such antigen molecule whose expression is positive in digestic tract tumor is named as carcinoembryonic antigen (CEA). Later, it was discovered that the expression of CEA antigen in tumor cells differentiated from endoderm cells is up to hundred folds higher than that of a normal cell, and thus it is an important antigen and marker for various human malignant tumors. CEAs are glycoproteins composed of carbohydrate chain and peptide chain with a molecular weight of about 180-200 kD. Due to the differences in the composition and origin of the carbohydrate chain, the biochemical property and immunogenicity of CEAs exhibit great heterogeneity, diversity, and non-homogenicity, and thus form a relatively big family of macromolecules. CEA molecule has many different antigenic epitopes, and these different epitopes are differently expressed in different normal tissues of adults, fetal organs, and various malignant tumor tissues, and the specificities thereof are also different. Hammarstrom et al. proposed in 1989 that CEA antigenic epitopes can be divided into 5 groups, i.e. Gold 1-5 (Gold classification). It is indicated in studies that the antigenic epitopes of Gold 1-5 groups are respectively located in domains A3, B2, B3, A1, and N of CEA molecules, wherein the A3 and B3 domains have low homology to other CEA related molecules, and they are relatively unique domains of CEA molecules.
CEA is mainly expressed on cell membrane and in cytoplasm of a cell, and it is also expressed in various germ layer tissues of 8-week old embryo. In the tissues of embryo older than 3 months, CEA is mainly expressed in gastrointestinal epithelial tissues; while the expression of CEA in adult tissues is significantly reduced or diminished, with only trace expression on the surface of colon epithelial cells. But CEA is highly expressed in many malignant tumors, including colorectal cancer, stomach cancer, lung cancer, breast cancer, pancreatic cancer, ovarial cancer, cervical cancer, prostate cancer, bladder cancer, gallbladder cancer and esophageal cancer, with a positive rate up to 50-90%. CEA is also highly expressed in metastatic lesions of these malignant tumors, and the expression levels are higher than the primary lesions. Among these tumors, the CEA expression in colorectal cancer is the highest in terms of both positive rate (than 95%) and intensity. CEA is highly expressed in almost all the colorectal cancer tissues, and the expression level and positive rate of CEA in metastatic lesions such as liver metastatic lesions are significantly higher than the primary lesions. It has also been proved in many studies that the expression of CEA in malignant tumors is closely related to the burden, stage, metastasis, and prognosis of tumors. Therefore, CEA has been widely recognized a specific molecular marker for malignant tumors, making it one of the best targets for targeted therapy and diagnosis of tumors.
CEA-positive malignant tumor has a high incidence rate, involving a huge number of patients, making it one of the most threatening diseases for the health of people in the world. For example, colon cancer with high expression of CEA is one of the most commonly seen malignant tumors. The incidence rate of colorectal cancer in European and American developed countries is No. 3 among all the malignant tumors, and the mortality rate thereof in No. 2. The newly developed cases worldwide are more than one million each year, and over 529,000 patients die of colorectal cancer. Each year there are nearly 400,000 newly developed colorectal cancer patients in China, and nearly 200,000 of colorectal cancer patients die due to refractory to treatment. Up to now, FDA has only approved 4 commonly used chemotherapy medicaments for colon cancer: fluorouracie, irinotacan, oxaliplatin, and capecitabine. These currently available chemotherapy medicaments and chemotherapy regimes as postoperative adjunctive treatment can reduce the recurrence rate of colorectal cancer to about 15%, and improve and increase the five-year survival rate to about 10-13%. Antibody targeted medicament is another type of new medicaments that have been developed during the last decade for treating malignant tumors. In the clinical treatment of some hematological system tumors, such as non-Hodgkin lymphoma etc., it has showed significant therapeutic effect, and can increase the five-year survival rate of patients. As for radioactive antibody targeting therapeutic agent using CEA antigens as target, currently no CEA antibody medicament has been approved for clinical use. But two CEA antibody radioactive immuno-therapeutic agents have been approved for phase I, II clinical trials. One is 131I-hMN-14 antibody medicament, i.e. 131I coupled recombinant humanized anti-CEA antibody hMN-14, which was developed in 1999 by Immunomedics Corp. of USA; and currently the phase II clinical trial for treating drug-resistant metastasis in advanced colorectal cancer has almost been finished, and it has entered the phase III clinical trial. Another anti-human CEA antibody medicament is cT84.66 human/mouse chimeric antibody coupled with radioactive nuclide 90y, which is developed under the approval of FDA by City of Hope National Medical Center of USA; currently the phase I clinical trial for treating advanced malignant tumors has been finished. However, the above two CEA antibody medicaments still have the some problems, such as the specificity needs to be further improved, the toxic and side effects need to be further reduced; the affinity of antibody is over high, which tends to cause the occurrence of affinity barrier during the targeting radioactive immunotherapy, and thereby significantly influence the therapeutic effect, etc. There is a need for new anti-CEA antibody to overcome the problems of anti-CEA antibodies of the prior art.
It has been concluded in numerous prior studies that, the binding specificity and affinity of an antibody are both predominantly determined by the amino acid sequences of the light chain and heavy chain super variable regions (also referred to as complementary determinant regions, and CDRs in abbreviation). U.S. Food and Drug Administration (FDA) has affirmed in its instructive principles that, all the antibodies of the same type that have the same complementary determinant region belong to one antibody. Accordingly, after obtaining the CDR of one antibody that has clinical therapeutic value, the amino acid sequences of its non-CDR regions can readily be changed through various established and well-known techniques, so as to obtain variants with same or even better biological activities.